Visna is a paralytic condition of sheep caused by the prototype of the lentivirus subfamily or retroviruses which now includes the agent of AIDS. The persistence and dissemination of virus despite host defenses, and the slow evolution of this infection are largely consequences of restricted gene expression. This proposal addresses at the organismal level the mechanisms by which this restriction is imposed. Genetic manipulations of viral DNA will be coupled with single and double label in situ hybridization and immunocytochemical assays to analyze the basis for the block in gene expression. This understanding will provide the basis for the design and testing of antisense and defective viruses as new approaches to the control of slow infections by lentiviruses and other intracellular pathogens.